Obesity is an increasingly common health problem in the U.S. and throughout the developed world. Approximately two-thirds of the U.S population is currently obese or overweight. While the recent epidemic is being driven primarily by environmental factors, there is strong evidence for unknown genetic factors that significantly contribute to an individual's propensity for weight gain. To better understand these genetic factors, we have studied C57BL/6J and A/J mice which respond differently to a calorie-rich environment. Despite similar physiology under normal conditions, C57BL/6J mice become obese and develop many of the symptoms of metabolic syndrome while A/J mice remain relatively lean. I have mapped a genetic factor that contributes to this strain difference in adiposity to a region on chromosome 6 that contains only a single gene, Cntnap2. There are 2 amino acid residues in CNTNAP2 that differ between C57BL/6J and A/J. These variants may lead to functional differences in the encoded protein in these two strains, thereby contributing to the difference in obesity susceptibility. We propose to study the role of Cntnap2 and a functionally related gene in obesity using approaches that integrate genetics, physiology, and biochemistry. A knockout mouse model will be generated to study the role of Cntnap2 in adiposity and energy balance as well as a number of clinically important comorbidities of obesity. The experiments proposed will greatly contribute to our scientific understanding of the molecular mechanisms underlying obesity and diabetes. Dr. Buchner's prior training has focused on the genetics of complex disease. This proposal aims to complement this training, with additional career development activities in the fields of physiology and mitochondrial biochemistry. This will be attained through additional coursework, hands-on experience with a team of experts in fields relevant to the proposed research, and significant mentoring from Dr. Nadeau and Dr. Charles Hoppel who are internationally recognized experts in their fields of genetics (Nadeau) and mitochondrial biochemistry (Hoppel). In addition to specific metabolism-related training activities, CWRU and the Department of Genetics will provide a rich mentoring environment for career development. Available activities include weekly scientific seminars, journal clubs, postdoctoral training programs, and many others. Another important component of the career development plan will be attending and presenting at national and international research conferences. Conferences will include an annual Keystone Symposium on obesity and diabetes and an annual Mitochondrial Medicine Conference. The mentoring by Drs. Nadeau and Hoppel, and collaborations with a team of accomplished investigators, will provide an exceptional environment to learn new skills and knowledge that will assist Dr. Buchner as he seeks to become a highly productive independent investigator at an academic institution. PUBLIC HEALTH RELEVANCE: Given the tremendous health impact of obesity, it would be of great benefit to identify the genes that underlie a mouse model of complex genetic obesity. This may lead to the identification of similar factors in humans that predispose individuals to significant weight gain and allow these individuals to modify their lifestyle accordingly. Additionally, identifying variation in genes or pathways with significant effects on weight gain may suggest potential therapeutic targets for safe and effective pharmaceutical intervention.